Project Summary/Abstract Multiple sclerosis is a devastating disease of the central nervous system that affects thousands of US veterans. MS frequently initially presents as temporary tingling or numbness in extremities or blurred vision. However, with time these events result in an accumulation of deficits leading to irreversible motor, sensory and cognitive dysfunction. Presently, there are no cures for MS. Treatment are available but their efficacy is highly variable and loss of motor function appears irreversible. Although classically described as a demyelinating disease, more recent studies have shown that axonal pathology is prevalent in MS and that this axonal pathology may be responsible for the irreversible loss of function associated with the disease. Here, we present strong preliminary data that challenge this view of MS. We show that a specific domain along the axon, known as the axon initial segment is structurally disrupted independent of demyelination indicating that axonal pathology in MS is a primary event and not merely consequential to demyelination. Structural disruption of the axon initial segment is functional devastating to the CNS since it is within the initial segment where i is decided whether an action potential will be generated. If our hypothesis is current, then disease onset does not parallel demyelinating episodes but occurs significantly earlier. Although our findings could revolutionize the view of MS onset, more importantly, we present strong preliminary data that disruption of the axon initial segment is reversible. Presently, we provide morphologic data suggesting reversibility. In this proposal we will test functional reversibility. Together, the studies outlined in this proposal are designed to challenge the current thinking of MS onset and the pathologic mechanisms that mediate the earliest stages of the disease. Moreover, we will further investigate the possibility that dysfunction that results form MS is reversible.